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Summary

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

Pruritus is an unpleasant sensation of the skin, which triggers a desire to scratch or rub. The chronic form (≥6 weeks’ duration) often occurs as a side effect of many diseases and is usually accompanied by a high loss in quality of life for patients, especially in cases in which the symptom is chronic without adequate treatment options. In recent years, the situation improved continuously, guidelines for chronic pruritus have been defined and standard medications have been proposed. For many reasons, there are still patients who are unable to obtain relief. New therapeutic approaches are therefore urgently needed. Blocking the neuropeptide substance P is a promising strategy; substance P mediates clinically relevant pro-inflammatory effects by binding to the neurokinin 1 receptor (NK-1R). This led us to hypothesize that NK-1R antagonists are promising therapeutic options for chronic pruritus. Several international case series have meanwhile proven the antipruritic effect of the NK-1R antagonist aprepitant for various forms of chronic pruritus. Initiation of clinical trials with new NK-1R-antagonists as a new therapeutic option continues this trend.


Clinical problem

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

Pruritus is an unpleasant sensation of the skin, which triggers a desire to itch or rub. Besides the acute form, which may indicate the presence of an irritating foreign body, chronic pruritus (duration ≥6 weeks) usually occurs in the context of an underlying disease. Various disease entities may cause pruritus and cover a spectrum from dermatoses (atopic dermatitis, urticaria, psoriasis) and systemic diseases (chronic kidney failure) to neurological (multiple sclerosis) and psychiatric diseases. In many cases, the pruritus does not match the clinical course of the underlying disease. Chronic pruritus (CP) may precede the onset of the underlying disease or may continue while the underlying disease is successfully treated or in remission. CP severely affects the patients’ quality of life, mainly because of the persistent symptoms and lack of therapeutic options, as well as through through feelings of embarrassment when secondary lesions become visible and sleep disturbances, which may combine to cause reactive depression [1]. Current epidemiologic studies indicate a lifetime prevalence of up to 23% in the adult population, with minimal gender-specific differences [2]. The wide variety of potential pathomechanisms and underlying pathologies challenge the clinician.

The pathogenesis is complex and poorly elucidated. It is assumed that CP pathomechanisms differ between the various underlying diseases. In atopic dermatitis, interleukin (IL-) 31 is presumably involved in pruritus induction during the acute inflammatory phase, while it does not play any role in other CP forms [3]. Peripheral and central neuronal sensitization processes are assumably involved in pruritus chronification [4]. In experimental and clinical studies, various neuronal receptors and mediators have during the last years been shown to be involved in neuronal sensitization [5], examples being cutaneous Mas-related G-protein coupled receptors (Mrgprs), Transient Receptor Potential (TRP) subtypes such as TRPV1 or TRPV3 and Nerve Growth Factor. The human subtype MrgprX1 is involved in chloroquine-induced pruritus, while other subtypes may be involved in other forms of CP and may thus constitute potential therapeutic targets. Other receptors are already addressed therapeutically, although the associated pruritogenic mechanisms remain to be elucidated in detail. Nalfurafine, a spinal κ-opioid receptor agonist has proven effective for the treatment of nephrogenic pruritus [6], while mu- opioid receptor antagonists (naltrexone, naloxone) are used in cholestatic pruritus. It seems likely that the respective opioid receptors are involved in differential CP pathophysiology, although this remains to be proven. In spite of scientific advances during the last years, few candidates as therapeutic targets have been transferred successfully from bench to bedside, and the demand for novel treatment modalities to supplement the current standard medications remains high. Current S2k guidelines for CP recommend antihistamines, anticonvulsives, opioid antagonists and antidepressants [7]. These therapeutic options alleviate the symptoms in a number of patients but rarely make the patient completely symptom-free. In addition, considerable side effects often limit the long-term use of these substances.

Research question and hypothesis

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

The neuropeptide substance P (SP) and its neurokinin-1 receptor (NK-1R) have proven to be promising targets for therapeutic interventions targeting CP. SP is a critical mediator both in the skin and the CNS during pruritus induction and maintenance. Case reports suggest a modification of NK-1R activity through specific antagonists as a suitable therapeutic option for CP.

Research in practice

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

Substance P is a short neuropeptide (11 amino acids; Arg-Pro-Lys-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) of the tachykinin family, which is synthesized and liberated from CNS neurons, peripheral capsaicin-sensitive primary afferent neurons and capsaicin-insensitive intrinsic GIT neurons, as well as non-neuronal inflammatory cells [8]. As an endogenous ligand, SP preferentially binds to the G-protein coupled NK-1R expressed in the CNS as well as immune cells and cutaneous keratinocytes and mast cells [9]. Upon depolarization, non-myelinated C fibers release SP into the surrounding tissues. Although rapidly degraded by angiotensin-converting enzyme (ACE) and cutaneous neutral endopeptidase (NEP), SP has various efferent effects. SP binds to NK-1R on keratinocytes and fibroblasts, thereby stimulating the secretion of interferon γ, IL-1β and IL-8. On mast cells, NK-1R binding leads to degranulation and secretion of histamine, leukotriene B4, prostaglandin D2, tumor necrosis factor α and vascular endothelial growth factor (VEGF); on vessels, this leads to vasodilatation and neurogenic inflammation whose clinical symptoms may include erythema, edema and pruritus [9].

We have shown the clinical relevance of pro-inflammatory SP effects [10]. In mice with a heterozygous depletion of somatic ACE, in which cutaneous neuronal SP was depleted by topical capsaicin treatment, inflammatory ear swelling in a DNFB inflammation model was significantly reduced. Similar effects were obtained by pretreatment with a systemic NK-1R antagonist, leading to the hypothesis that systemic NK-1R antagonists may contribute to an alleviation of inflammatory pruritus. Aprepitant is a highly selective NK-1R antagonist approved for the prevention and therapy of chemotherapy-induced nausea and vomiting. In prior phase II trials, aprepitant it failed to prove effective in the therapy of acute pain and depression, and has therefore not been developed further for related indications. In our first patients treated with aprepitant for CP in 2006, a remarkable antipruritic effect was shown. Data obtained from another 20 consecutively enrolled patients showed a statistically significant reduction of long-term CP, which was reduced by 3.5 points on a visual analogue scale within one week [11]. In this open, not placebo-controlled, proof-of-concept study, best results were obtained in patients with atopic predisposition and in prurigo nodularis. For both groups, an elevated density of SP-positive dermal nerve fibers has been described [12-14]. Elevated cutaneous SP levels were found in patients with pruritus-associated diseases of the skin [15-17], while an influence on pruritogenesis in atopic dermatitis [18] and cholestatic pruritus [19] has been proposed.

The effect we observed has been confirmed simultaneously by other international research groups. So far, data from more than 110 responders to aprepitant 80–125 mg/d have been published in case reports and case series, indications including pruritus in cutaneous T-cell lymphoma, paraneoplastic and drug-induced (novel antineoplastic substances such as Erlotinib) pruritus. Randomized controlled trial data are not available; our data may also be compared only to the clinical course prior to treatment initiation. In an intraindividual comparison, aprepitant had a more rapid onset and stronger antipruritic effect than prior therapy protocols which were in accordance with current guidelines, which indicates its antipruritic potential, while placebo-controlled trials remain to be conducted. The therapeutic concept of NK-1R antagonists for CP has been recognized due to confirming data from a number of international research groups, and has led to the development of new substances and initiation of randomized controlled trials. Currently, phase II trials of atopic dermatitis and prurigo nodularis, as well as a phase IV trial of aprepitant for cutaneous T-cell lymphoma, are being conducted. Funding from the Clinical Trial Program of the German Federal Ministry of Education and Research has enabled us to conduct a multicentric Phase II trial of aprepitant for prurigo nodularis.

Conclusions for clinical practice

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

A deeper understanding of the neurobiology of CP has contributed to the identification of novel therapeutic options, illustrated here for substance P. In a translational research project, an NK-1R antagonist could be validated as a promising candidate for the treatment of CP in an animal model. Current trials address indications characterized by severe pruritus and an urgent need for potent, antipruritic therapeutic options. These developments are not only of high clinical relevance, but underline the need for a targeted individual assessment and therapy of CP, which has to be interdisciplinary and independent of the underlying disease.

Funding

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References

This project has been supported by the German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung (BMBF 01KG1305).

References

  1. Top of page
  2. Summary
  3. Clinical problem
  4. Research question and hypothesis
  5. Research in practice
  6. Conclusions for clinical practice
  7. Funding
  8. References